repurposing empagliflozin for dmd-associated cardiomyopathy in children 6-18 years of age

Conditions: DMD-associated Dilated Cardiomyopathy

Summary: this study aims at exploring the use of empagliflozin in children and adolescents 6-18 years old with duchenne muscular distrophy (dmd) - associated cardiomyopathy. this molecule is effective in reducing hospitalizations and mortality in adults with heart failure and is used in adolescents with type 2 diabetes mellitus, but little is known on children and adolescents with heart failure. particularly, the best dose to use in this population is currently unknown. this trial aims to: 1. define a dose rationale for this indication and age group (pharmacokinetic study), 2. assess and monitor safety, 3. assess ease-of-swallow, 4. explore middle-term (3-6 months) efficacy and efficacy markers. participants will be asked to attend 5 study visits over 6 months, and one end-study visit 2-12 weeks thereafter. visit 1 will entail an 8h day-hospital stay, while visits 2, 3, 4 and 5, as well as the end-study visit, will be outpatient clinics (approximately 2h). participants will be asked to take the studied drug once daily during the 6 months of the study period. no comparison group is foreseen for this study.

cardiac disease represents the main life-limiting condition in duchenne muscular dystrophy (dmd). it is important to recognize and address this early in the disease course. because of lack of dmd specific drugs, present attitudes for established dmd-related cardiomyopathy ground on current treatment for heart failure. unfortunately, however, current heart failure therapy in paediatrics is still unsatisfactory, with high in-hospital (7-26%), and 5-year mortality (30%-50%). furthermore, mortality rate for dmd cardiomyopathy is worse than similarly aged idiopathic dilated cardiomyopathy (dcm) patients. among the recent improvements in adult heart failure management, the sodium glucose transporter type 2 inhibitors (sglt2i) dapagliflozin and empagliflozin were found to reduce cardiovascular death or worsening heart failure by 25% on top of optimal medical therapy. indeed, since 2021, they have been recommended as part of standard heart failure therapy. in the past, paediatric heart failure trials often failed, mainly because of suboptimal dose or inappropriate formulations and endpoints. this phase ii.a, open-label trial is designed to characterize pharmacokinetics (primary outcome), ease-of-swallow, safety and explore potential efficacy markers (secondary outcomes) of empagliflozin in 12 children and adolescents with dmd-related cardiomyopathy, so to inform the design and performance of subsequent, state-of-the-art, high-quality efficacy trials. participants will receive empagliflozin during 6 months. they will have 5 visits, one end-study visit and 7 to 8 pharmacokinetic samples. the timing of these samples will be optimized exploiting contemporary modeling and simulation techniques. safety evaluation will occur throughout the study, while ease-of-swallow will be evaluated at visit 1, and efficacy markers at visits 1, 4 and 5. pharmacokinetic modeling will characterize primary and secondary pharmacokinetic parameters and allow to define the optimal paediatric dose, informing both current compassionate-care use and the design of future efficacy trials.

Eligibility criteria:
inclusion criteria: * children or adolescents 6 to 18 years of age with dmd-associated cardiomyopathy, followed either as in- or outpatients, will be eligible for inclusion. * currently on heart failure medication (any drug or any combination). * patients should potentially benefit from adding a sglt2i (as judged by the treating physician and the pi or co-pi). * patients need to be on stable medical treatment, defined as no new heart failure drug started over the preceding 2 weeks and no major drug dose modification (apart minor adaptations, like weight adaptations, rounding or formulation changes) during the 2 weeks prior to enrolment. * adolescents, respectively parents or caregivers of children, capable of giving informed consent. * ability to tolerate a cardiac mri investigation without the need of general anaesthesia. exclusion criteria: * inability to understand and go through the informed consent procedure. * inability to receive medications per os or through a nasogastric tube. * patients on either insulin or metformin will be excluded from participation. this implies the exclusion of patients with diabetes mellitus (either type 1 or type 2 or other rare forms) necessitating either insulin or metformin. * type 1 diabetes mellitus or any underlying metabolic disease associated with hypoglycaemias. * body weight \<15kg. * current smokers (defined as \>1 cigarette/week). * use of any other nicotine-delivering product (e.g. nicotine patches). * any known illicit drug abuse. * active chronic hbv, hcv or hiv. * any major surgery within 4 weeks of first dose administration. * blood transfusion recipient within 4 weeks of dose administration. * egfr \<45ml/min/1.73m2 (simplified schwartz formula or filler formula). * k+ \>6.5mmol/l. * blood glucose \<4mmol/l. * there are no blood pressure exclusion criteria foreseen, but participants need to be haemodynamically stable, as assessed by the local investigator. * sustained or symptomatic arrhythmia insufficiently controlled with drug and/or device therapy. * cardio-surgical procedure within the 2 months prior to visit 1, or interventional cardiac catheterization within 2 weeks prior to visit 1, or the patient is planned to undergo cardiac surgery or an interventional cardiac catheterization during the study period (i.e. in the 6 months following visit 1). * post-menarchal female patients of childbearing potential cannot be included. * known lactose intolerance, galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption. * known allergies to excipients of commercially available empagliflozin tablets. * significant medical history of active severe medical disease. * significant liver disease, child pugh class c, or significant laboratory abnormalities at enrolment. * significant gastroenterological or hepatic disease that could significantly impair absorption or metabolism of orally administered drugs. * any medical co-morbidity, which is deemed incompatible (or only with relevant risk) with study participation by the treating clinician and/or the study investigator. * active urinary tract infection (being treated with antibiotics at the moment of visit 1) or other relevant bacterial infection, as judged by the treating clinician and/or the study investigator. * the patient is currently participating in another interventional clinical trial or has participated in such a trial during the \<14 days before visit 1 (or if enrolment in this study is incompatible with the protocol of that preceding trial).